Efficacy and safety of a nanoparticle therapeutic vaccine in patients with chronic hepatitis B: A randomized clinical trial.

BACKGROUND AND AIM: HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB. APPROACH AND RESULTS: A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA < 2,000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 µg εPA-44-treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo. CONCLUSIONS: Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).

NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels.

BACKGROUND: Hydrocephalus is a severe complication of intracerebral hemorrhage with ventricular extension (ICH-IVH) and causes cerebrospinal fluid (CSF) accumulation. The choroid plexus epithelium plays an important role in CSF secretion and constitutes the blood-CSF barrier within the brain-immune system interface. Although the NLRP3 inflammasome, as a key component of the innate immune system, promotes neuroinflammation, its role in the pathogenesis of hydrocephalus after hemorrhage has not been investigated. Therefore, this study aimed to investigate the potential mechanism of NLRP3 in hydrocephalus to discover a potential marker for targeted therapy. METHODS: A rat model of hydrocephalus after ICH-IVH was developed through autologous blood infusion in wild-type and Nlrp3-/- rats. By studying the features and processes of the model, we investigated the relationship between the NLRP3 inflammasome and CSF hypersecretion in the choroid plexus. RESULTS: The ICH-IVH model rats showed ventricular dilation accompanied by CSF hypersecretion for 3 days. Based on the choroid plexus RNA-seq and proteomics results, we found that an inflammatory response was activated. The NLRP3 inflammasome was investigated, and the expression levels of NLRP3 inflammasome components reached a peak at 3 days after ICH-IVH. Inhibition of NLRP3 by an MCC950 inflammasome inhibitor or Nlrp3 knockout decreased CSF secretion and ventricular dilation and attenuated neurological deficits after ICH-IVH. The mechanism underlying the neuroprotective effects of NLRP3 inhibition involved decreased phosphorylation of NKCC1, which is a major protein that regulates CSF secretion by altering Na+- and K+-coupled water transport, via MCC950 or Nlrp3 knockout. In combination with the in vitro experiments, this experiment confirmed the involvement of the NLRP3/p-NKCC1 pathway and Na+ and K+ flux. CONCLUSIONS: This study demonstrates that NKCC1 phosphorylation in the choroid plexus epithelium promotes NLRP3 inflammasome-mediated CSF hypersecretion and that NLRP3 plays an important role in the pathogenesis of hydrocephalus after hemorrhage. These findings provide a new therapeutic strategy for treating hydrocephalus.

HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein.

BACKGROUND AND AIMS: Cancer is typically considered as a genetic and epigenetic disease. Although numerous studies have indicated that an aberrant structure, function, or expression level of epigenetic enzymes contribute to many tumor types, precisely how the epigenetic mechanisms are involved in the hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unknown. APPROACH AND RESULTS: In this study, we found that the WD repeat domain 5 protein (WDR5)-a core subunit of histone H3 lysine 4 methyltransferase complexes, which catalyze the generation of histone H3 lysine 4 trimethylation (H3K4me3) modification-is highly expressed in HBV-related HCC and promotes HCC development. WDR5 plays a critical role in HBV-driven cell proliferation and tumor growth in mice, and the WDR5-0103 small-molecule inhibitor of WDR5 activity compromises HBV- and hepatitis B x protein (HBx)-driven tumor proliferation. The aberrantly high WDR5 protein level was found to involve HBx through its stabilization of the WDR5 protein by inhibiting the interaction between the damage-specific DNA-binding protein 1/cullin-4 and WDR5, causing decreased ubiquitination of the WDR5 protein. HBx was found to colocalize with WDR5 on chromatin genome wide and promotes genome-wide H3K4me3 modification by means of WDR5. Furthermore, the recruitment of HBx to promoters of target genes relied on its interaction with WDR5 through its α-helix domain. WDR5 was also found to promote HBV transcription through H3K4 modification of covalently closed circular DNA minichromosome, and WDR5-0103 was able to inhibit HBV transcription. Finally, the in vitro and in vivo data further proved that HBx exerted its tumor-promoting function in a WDR5-dependent manner. CONCLUSIONS: Our data reveals that WDR5 is a key epigenetic determinant of HBV-induced tumorigenesis and that the HBx-WDR5-H3K4me3 axis may be a potential therapeutic target in HBV-induced liver pathogenesis.

MitoQ attenuates brain damage by polarizing microglia towards the M2 phenotype through inhibition of the NLRP3 inflammasome after ICH.

Microglial phenotype plays an important role in secondary injury after intracerebral haemorrhage (ICH), with M1 microglia promoting inflammatory injury and M2 microglia inhibiting neuroinflammation and promoting haematoma absorption. However, there is no effective intervention for regulating the phenotypic transformation of microglia after ICH. This study aimed to elucidate the protective effect of MitoQ, a selective mitochondrial ROS antioxidant, against microglial M1 state polarization and secondary brain injury. The in vivo data showed that MitoQ attenuated neurological deficits and decreased inflammation, oedema and haematoma volume after ICH. In addition, MitoQ decreased the expression of M1 markers and increased the expression of M2 markers both in vivo and in vitro after ICH. Mechanistically, MitoQ blocked overproduction of mitochondrial ROS and activation of the NLRP3 inflammasome in FeCl2-treated microglia. Moreover, NLRP3 siRNA shifted FeCl2-treated microglia from the M1 to the M2 cells, revealing that MitoQ-induce polarization states may be mediated by the mitochondrial ROS/NLRP-3 pathway. In summary, MitoQ alleviates secondary brain injury and accelerates haematoma resolution by shifting microglia towards the M2 phenotype after ICH.

Hepatitis B virus induces IL-23 production in antigen presenting cells and causes liver damage via the IL-23/IL-17 axis.

IL-23 regulates myriad processes in the innate and adaptive immune systems, and is a critical mediator of the proinflammatory effects exerted by Th17 cells in many diseases. In this study, we investigated whether and how hepatitis B virus (HBV) causes liver damage directly through the IL-23 signaling pathway. In biopsied liver tissues from HBV-infected patients, expression of both IL-23 and IL-23R was remarkably elevated. In vivo observations also indicated that the main sources of IL-23 were myeloid dendritic cells (mDCs) and macrophages. Analysis of in vitro differentiated immature DCs and macrophages isolated from healthy donors revealed that the HBV surface antigen (HBsAg) efficiently induces IL-23 secretion in a mannose receptor (MR)-dependent manner. Culture with an endosomal acidification inhibitor and the dynamin inhibitor showed that, upon binding to the MR, the HBsAg is taken up by mDCs and macrophages through an endocytosis mechanism. In contrast, although the HBV core antigen (HBcAg) can also stimulate IL-23 secretion from mDCs, the process was MR- and endocytosis-independent. In addition, IL-23 was shown to be indispensible for HBsAg-stimulated differentiation of naïve CD4(+) T cells into Th17 cells, which were determined to be the primary source of IL-17 in HBV-infected livers. The cognate receptor, IL-17R, was found to exist on the hepatic stellate cells and mDCs, both of which might represent the potential target cells of IL-17 in hepatitis B disease. These data provide novel insights into a yet unrecognized mechanism of HBV-induced hepatitis, by which increases in IL-23 expression, through an MR/endocytosis-dependent or -independent manner, produce liver damage through the IL-23/IL-17 axis.

A novel splice variant of folate receptor 4 predominantly expressed in regulatory T cells.

BACKGROUND: Regulatory T cells (Tregs) are required for proper maintenance of immunological self-tolerance and immune homeostasis. Folate receptor 4 (FR4) is expressed at high levels in transforming growth factor-beta (TGF-ß)-induced Tregs and natural Tregs. Moreover, antibody-mediated targeting of FR4 is sufficient to mediate Treg depletion. RESULTS: In this study, we describe a novel FR4 transcript variant, FR4D3, in which exon 3 is deleted. The mRNA of FR4D3 encodes a FR4 variant truncated by 189 bp. FR4D3 was found to be predominantly expressed in CD4(+)CD25(+) Treg cells. Overexpression of FR4D3 in CD4(+)CD25(+) Treg cells in vitro stimulated proliferation, which may modulate the ability of these cells to bind and incorporate folic acid. CONCLUSIONS: Our results suggested that high levels of FR4D3 may be critical to support the substantial proliferative capacity of Treg cells.

Inhibiting Microglia-Derived NLRP3 Alleviates Subependymal Edema and Cognitive Dysfunction in Posthemorrhagic Hydrocephalus after Intracerebral Hemorrhage via AMPK/Beclin-1 Pathway.

For posthemorrhagic hydrocephalus (PHH) patients, whether occur subependymal edema indicates poor outcomes, partially manifested as cognitive impairment. In the brain, NLRP3 inflammasome mainly derived from microglia/macrophages is involved in proinflammatory and neurodeficits after hemorrhage, and autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggest that NLRP3 inflammasome and autophagy played an essential role after intracerebral hemorrhage (ICH). We aimed to dissect the mechanisms underlying subependymal edema formation and cognitive dysfunction. Here, based on the hydrocephalus secondary to ICH break into ventricular (ICH-IVH) in rats, this study investigated whether microglia/macrophage-derived NLRP3 induced subependymal edema formation and neuron apoptosis in subventricular zones (SVZ). In the acute phase of ICH-IVH, both the expression of NLRP3 inflammasome of microglia/macrophages and the autophagy of neurons were upregulated. The activated NLRP3 in microglia/macrophages promoted the release of IL-1beta to extracellular, which contributed to excessive autophagy, leading to neurons apoptosis both in vivo and in vitro through the AMPK/Beclin-1 pathway combined with transcriptomics. Administration of MCC950 (NLRP3 inflammasome specific inhibitor) after ICH-IVH significantly reduced edema formation and improved cognitive dysfunction. Thus, inhibiting NLRP3 activation in SVZ may be a promising therapeutic strategy for PHH patients that warrants further investigation.

Inhibition of plasma kallikrein mitigates experimental hypertension-enhanced cerebral hematoma expansion.

RATIONALE: Hematoma expansion (HE) aggravates brain injury after intracerebral hemorrhage (ICH) and hypertension is a key contributor to HE. Plasma kallikrein (PK) is involved in hemorrhagic transformation in ischemic stroke mice. This study was conducted to explore the role of PK in HE in hypertensive ICH. METHODS: Hypertension was achieved by continuous infusion of angiotensin II (Ang II) with an osmotic pump in C57BL/6 mice. ICH was achieved by stereotactic intrastriatal injection of blood. PK-specific antibody and platelet glycoprotein VI (GPVI) agonists were administered to intervene in hematoma expansion. The hematoma volume was indicated by the erythrocyte components hemoglobin and carbonic anhydrase-1 in the ipsilateral brain hemisphere. RESULTS: Ang II-induced hypertensive mice showed enhanced hematoma expansion and worsened neurologic deficits after ICH modeling. Moreover, intrastriatal injection of blood from Ang II-treated mice into normal mice increased the area of secondary hemorrhage more than blood from untreated mice. Mechanistically, elevated PK was found in Ang II-infused mice whereas, inhibition of PK and administration of the GPVI agonist convulxin decreased hematoma expansion and improved neurologic deficits after ICH. CONCLUSIONS: These findings suggest that PK inhibition and GPVI agonist treatment might serve as potential methods to intervene in HE after ICH.

Identification of two novel HLA-A*0201-restricted CTL epitopes derived from MAGE-A4.

MAGE-A antigens belong to cancer/testis (CT) antigens that are expressed in tumors but not in normal tissues except testis and placenta. MAGE-A antigens and their epitope peptides have been used in tumor immunotherapy trials. MAGE-A4 antigen is extensively expressed in various histological types of tumors, so it represents an attractive target for tumor immunotherapy. In this study, we predicted HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) epitopes of MAGE-A4, followed by peptide/HLA-A*0201 affinity and complex stability assays. Of selected four peptides (designated P1, P2, P3, and P4), P1 (MAGE-A4(286-294), KVLEHVVRV) and P3 (MAGE-A4(272-280), FLWGPRALA) could elicit peptide-specific CTLs both in vitro from HLA-A*0201-positive PBMCs and in HLA-A*0201/K(b) transgenic mice. And the induced CTLs could lyse target cells in an HLA-A*0201-restricted fashion, demonstrating that the two peptides are HLA-A*0201-restricted CTL epitopes and could serve as targets for therapeutic antitumoral vaccination.

Induced B7-H1 expression on human renal tubular epithelial cells by the sublytic terminal complement complex C5b-9.

The co-inhibitory molecule B7-H1 has been broadly detectable on human inflammatory renal tubular epithelial cells (TECs) and is proposed to limit tubular damage through down-regulation of tubulointerstitial infiltration T cell activation. Nevertheless, factors that initiate B7-H1 expression on TECs remain unclarified. The terminal complement complex C5b-9, which deposits diffusely on tubules and glomerules of diseased kidneys, is now recognized as a mediator that triggers cellular activation rather than inducing cell death. Whether the up-regulation of B7-H1 on tubules is also induced by C5b-9 is uncertain. Here, after assembling functional sublytic C5b-9 on the membranes of TECs based on purified complement components, we found that B7-H1 gene transcription and protein synthesis was enhanced by C5b-9. Promoter constructs in a luciferase assay, site-directed mutagenesis and laser scanning confocal microscopy assay (LSCM) revealed that the transcription factor NF-kappaB is primarily responsible for C5b-9-mediated B7-H1 expression. To further detect the physiologic function of B7-H1, triggering B7-H1 with its agonist mAb (clone 5H1) profoundly enhanced Fas expression on C5b-9-treated TECs and thus induced TEC apoptosis. Interestingly, pretreatment of TECs with Fas blocking antibodies prevented this effect. Our results propose that C5b-9 regulates tubular pathogenesis in glomerulonephritis or other renal autoimmune diseases, possibly through enhances cell apoptosis mediated by B7-H1 signals, in addition to it directly promotes tubular damage.

Quantitative Iron Neuroimaging Can Be Used to Assess the Effects of Minocycline in an Intracerebral Hemorrhage Minipig Model.

Iron-mediated toxicity is a key factor causing brain injury after intracerebral hemorrhage (ICH). This study was performed to investigate the noninvasive neuroimaging method for quantifying brain iron content using a minipig ICH model and assess the effects of minocycline treatment on ICH-induced iron overload and brain injury. The minipig ICH model was established by injecting 2 ml of autologous blood into the right basal ganglia, which were then subjected to the treatments of minocycline and vehicle. Furthermore, the quantitative susceptibility mapping (QSM) was used to quantify iron content, and diffusion tensor imaging (DTI) was performed to evaluate white matter tract. Additionally, we also performed immunohistochemistry, Western blot, iron assay, Perl's staining, brain water content, and neurological score to evaluate the iron overload and brain injury. Interestingly, we found that the ICH-induced iron overload could be accurately quantified by the QSM. Moreover, the minocycline was quite beneficial for protecting brain injury by reducing the lesion volume and brain edema, preventing brain iron accumulation, downsizing ventricle enlargement, and alleviating white matter injury and neurological deficits. In summary, we suggest that the QSM be an accurate and noninvasive method for quantifying brain iron level, and the minocycline may be a promising therapeutic agent for patients with ICH.

Lithium treatment mitigates white matter injury after intracerebral hemorrhage through brain-derived neurotrophic factor signaling in mice.

Intracerebral hemorrhage (ICH), a subtype of stroke with high morbidity and mortality, occurs mainly in the basal ganglia and causes white matter injury (WMI), resulting in severe motor dysfunction and poor prognosis in patients. The preservation of the white matter around the hematoma is crucial for motor function recovery, but there is currently no effective treatment for WMI following ICH. Lithium has been widely used for the treatment of bipolar disorder for decades. Although the protective effects of lithium on neurodegenerative diseases and cerebral trauma have been studied in recent years, whether it can be used to alleviate WMI after ICH remains to be researched. The results of this study revealed that ICH caused significant functional and pathological abnormalities in mice. After LiCl was administered to mice with ICH, behavioural performance and electrophysiological functions were improved and ICH-induced white matter pathological injury, including myelin sheath and axonal degeneration, was ameliorated. Furthermore, LiCl treatment decreased the death of mature oligodendrocytes (OLGs) in ICH mice, which may have been attributed to the enhanced expression of brain-derived neurotrophic factor (BDNF) regulated by the LiCl-induced inhibition of glycogen synthase kinase-3ß (GSK-3ß). The decreased death of OLGs was closely associated with decreased destruction of the myelin sheath and alleviated degradation of the axons. In summary, this study suggests that the protective effect of lithium on WMI after ICH might be related to an increased level of BDNF and that LiCl treatment may be a potential therapeutic method to palliate WMI after ICH.

Nicotinamide riboside rescues angiotensin II-induced cerebral small vessel disease in mice.

AIMS: Hypertension is a leading cause of cerebral small vessel disease (CSVD). Currently, treatments for CSVD are limited. Nicotinamide riboside (NR) can protect against vascular injury and cognitive impairment in neurodegenerative diseases. In this study, the protective effects of NR against angiotensin - (Ang -)-induced CSVD were evaluated. METHODS: To explore the effects of NR in CSVD, C57BL/6 mice were infused with Ang -, and NR was added to the food of the mice for 28 days. Then, short-term memory, blood-brain barrier (BBB) integrity, and endothelial function were detected. Arteriole injury and glial activation were also evaluated. RESULTS: Our data showed that mice infused with Ang - exhibited decreased short-term memory function and BBB leakage due to decreased claudin-5 expression and increased caveolae-mediated endocytosis after 28 days. Furthermore, Ang - decreased the expression of α-smooth muscle actin (α-SMA) and increased the expression of proliferating cell nuclear antigen (PCNA) in arterioles and decreased the expression of neurofilament 200 (NF200) and myelin basic protein (MBP) in the white matter. These CSVD-related damages induced by Ang - were inhibited by NR administration. Moreover, NR administration significantly reduced glial activation around the vessels. CONCLUSION: Our results indicated that NR administration alleviated Ang --induced CSVD by protecting BBB integrity, vascular remodeling, neuroinflammation, and white matter injury (WMI)-associated cognitive impairment.

Inhibition of Mitochondrial ROS by MitoQ Alleviates White Matter Injury and Improves Outcomes after Intracerebral Haemorrhage in Mice.

White matter injury (WMI) is an important cause of high disability after intracerebral haemorrhage (ICH). It is widely accepted that reactive oxygen species (ROS) contributes to WMI, but there is still no evidence-based treatment. Here, mitoquinone (MitoQ), a newly developed selective mitochondrial ROS scavenger, was used to test its neuroprotective potential. The data showed that MitoQ attenuated motor function deficits and motor-evoked potential (MEP) latency prolongation. Further research found that MitoQ blunted the loss of oligodendrocytes and oligodendrocyte precursor cells, therefore reduced demyelination and axon swelling after ICH. In the in vitro experiments, MitoQ, but not the nonselective antioxidant, almost completely attenuated the iron-induced membrane potential decrease and cell death. Mechanistically, MitoQ blocked the ATP deletion and mitochondrial ROS overproduction. The present study demonstrates that the selective mitochondrial ROS scavenger MitoQ may improve the efficacy of antioxidant treatment of ICH by white matter injury alleviation.

A novel splice variant of FR4 predominantly expressed in CD4+CD25+ regulatory T cells.

Folate receptor 4 (FR4) is recently found as a lymphoid tissue specific protein. In this study, we have identified an alternative splicing variant of the FR4 gene from murine splenocytes, termed FR4v, which is almost identical to FR4 cDNA sequence except with the retained 108 bp intron 3 between exon 3 and 4 of FR4 gene. FR4v mRNA encodes a larger protein than FR4 and is constitutively expressed on CD4(+)CD25(+) regulatory T cell (Treg) membrane via a GPI anchor mechanism. Whether FR4v plays a redundant or unique functional role in Tregs should be investigated further in the future.

Identification of a common HLA-A*0201-restricted epitope among SSX family members by mimicking altered peptide ligands strategy.

The synovial sarcoma X breakpoint (SSX) gene family contains nine members. The SSX proteins are CT (cancer/testis) antigens and can be expressed in many tumor types. T cell immune response against SSX protein can be detected in tumor patients and mice expressing any SSX. Screening predominant protective epitopes might improve the low immunogenicity against these "self" CT antigens. Herein, we predicted HLA-A*0201-restricted epitopes for all nine SSX family members, followed by validation with epitope molecular modeling, peptide/HLA-A*0201 affinity, and binding stability assays. We obtained four highly homologous candidate epitopes with the high immunogenicity scores designated P1, P4, P5 and P6, from the nine SSX members. Each of the four candidates could elicit strong epitope-specific CTL immune responses, but P4 could evoke more interferon gamma (IFN-gamma)-producing T cells and more potent CTLs that could lyse more target cells. Importantly, almost all of the four epitopes induced CTLs could cross-lyse the mutual targets both in vitro in human PBMCs and HLA-A2.1/K(b) transgenic mice, but P4 showed superiority to other epitopes in term of cross-cytolysis. All of these results demonstrate that P4 can induce anti-tumor immunity in a fashion superior to other candidates, and may be the "common" CTL epitope among all SSX-expressing tumors. Due to its documented responses herein, P4 has potential application in peptide-mediated immunotherapy.

G protein-coupled estrogen receptor 1 negatively regulates the proliferation of mouse-derived neural stem/progenitor cells via extracellular signal-regulated kinase pathway.

G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) has been reported to play a wide range of function in the central nervous system (CNS). However, whether GPER1 is expressed by neural stem/progenitor cells (NSPCs) and its role has not been established. Here, we found the expression of GPER1 in mouse-derived NSPCs via western blot and immunofluorescent staining. Moreover, we revealed that specific activation of GPER1 by the agonist G1 decreased the proliferation of NSPCs in a dose-dependent manner. The neurosphere formation assay and Ki67 staining further demonstrated that activation of GPER1 inhibited the proliferation of NSPCs. Additionally, the inhibitory effect of G1 on the proliferation of NSPCs could be blocked by the specific GPER1 antagonist G15. Intriguingly, ERK pathway was involved in the negative effect of GPER1 on the proliferation of NSPCs, because the phosphorylation level of ERK in NSPCs was remarkably decreased during G1 treatment. However, the antagonist G15 reversed the down-regulated level of p-ERK. Knock-down GPER1 also reversed the inhibitory effect of G1 on NSPCs proliferation. Together, our results provide the first evidence that GPER1 is expressed by NSPCs and its activation negatively modulates the proliferation of NSPCs, highlighting the importance of GPER1 in regulating NSPC behaviors.

TRPA1 Activation-Induced Myelin Degradation Plays a Key Role in Motor Dysfunction After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating disease that is characterized by high morbidity and high mortality. ICH has an annual incidence of 10-30/100,000 people and accounts for approximately 10%-30% of all types of stroke. ICH mostly occurs at the basal ganglia, which is rich in nerve fibers; thus, hemiplegia is quite common in ICH patients with partial sensory disturbance and ectopic blindness. In the clinic, those symptoms are considered to originate from the white matter injury in the area, but the exact mechanisms are unknown, and currently, no effective drug treatments are available to improve the prognosis. Clarifying the mechanisms will contribute to the development of new treatment methods for patients. The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel that plays a role in inflammatory pain sensation and nociception and may be a potential regulator in emotion, cognition and social behavior. Here, we report that TRPA1 is involved in myelin damage and oxidative stress injury in a mouse ICH model. Intervention with the TRPA1 channel may be a new method to improve the motor function of patients in the early stage of ICH.

Modified behavioural tests to detect white matter injury- induced motor deficits after intracerebral haemorrhage in mice.

Motor function deficit induced by white matter injury (WMI) is one of the most severe complications of intracerebral haemorrhage (ICH). The degree of WMI is closely related to the prognosis of patients after ICH. However, the current behavioural assessment of motor function used in the ICH mouse model is mainly based on that for ischaemic stroke and lacks the behavioural methods that accurately respond to WMI. Here, a series of easy-to-implement behavioural tests were performed to detect motor deficits in mice after ICH. The results showed that the grip strength test and the modified pole test not only can better distinguish the degree of motor dysfunction between different volumes of blood ICH models than the Basso Mouse Scale and the beam walking test but can also accurately reflect the severity of WMI characterized by demyelination, axonal swelling and the latency of motor-evoked potential delay induced by ICH. In addition, after ICH, the results of grip tests and modified pole tests, rather than the Basso Mouse Scale and the beam walking test, were worse than those observed after intraventricular haemorrhage (IVH), which was used as a model of brain haemorrhage in non-white matter areas. These results indicate that the grip strength test and the modified pole test have advantages in detecting the degree of motor deficit induced by white matter injury after ICH in mice.

Protection from infection with severe acute respiratory syndrome coronavirus in a Chinese hamster model by equine neutralizing F(ab')2.

To warrant potential clinical testing, the equine anti-severe acute respiratory syndrome coronavirus (SARS-CoV) F(ab')(2) requires evaluation in as many animal models as possible. In this study, we established a new animal model, the Chinese hamster, susceptible to SARS-CoV infection. SARS-CoV could propagate effectively and sustain high levels for 1 wk in animal lungs. All animals were protected from SARS-CoV infection in preventive settings. Further, when used therapeutically this antibody led to an approximately 4-log(10) decrease in viral burden in infected animal lungs. The pathological changes in lungs correlated closely with the dose of antibody administered. The excellent preventive and therapeutic roles of equine anti-SARS-CoV F(ab')(2) in several animal models, including the novel Chinese hamster model described in this study, have provided exciting data concerning its potential clinical study.